The Human Immunodeficiency Virus (HIV) binds via its gp120 envelope protein with high affinity to the immunoregulatory cell surface molecule, CD4. The pathogenetic relevance of this interaction is subject to this proposal. We found that antibodies to gp120 bind to the CD4 molecule via gp120. The gp120/anti-gp120 complex aggregates CD4, modulates it and blocks the activation of T cells (Ca2+i mobilization) much like genuine anti-CD4. Based on this finding, we postulate that the HIV-infected immune system participates in its own destruction. CD4+ T cells replicate the virus and disseminate gp120, B lymphocytes make antibody to gp120. Gp120 and anti-gp120 synergize in downregulating CD4-dependent immune functions. Characteristic of anti-CD4 induced immunodeficiency in mice is a decline in CD4+ T cells and a loss of function of those CD4+ T cells not deleted. The same phenomenon is seen during the development of immunodeficiency in HIV-infected individuals. We propose here to define in the mouse parameters characteristic of anti-CD4-induced immunodeficiency in terms of CD4 mobility, aggregability and function (Aim 1). As an extension of these studies, we plan to investigate the development of immunodeficiency induced with anti-CD4 or gp120/anti-gp120 complexes in SCID mice reconstituted with a human immune system (Aim 2). We plan to apply parameters characteristic of CD4-mediated immunodeficiency obtained in these animal studies to assess immune function of T cells from HIV-infected individuals relative to the course of disease (Aim 4). We are interested also in identifying gp120 epitopes which participate in anti-gp120-mediated immune suppression (Aim 3).